RETRACTED: Oocyte and Somatic Cell Procurement for Stem Cell Research:
by Kyu Won Jung, Insoo Hyun
2006. The American Journal of Bioethics 6(1):W19

ARTICLE RETRACTED BY EDITORS

Rapid advances in human somatic cell nuclear transfer (SCNT) for stem cell research in South Korea (Hwang et al. 2005) have raised a number of new issues in research ethics. To date, most commentators have tended to focus on concerns surrounding human oocyte donation for stem cell science. For instance, one critic has claimed that it is unclear what ethical principles effectively governed the Korean oocyte donation consent process (Caplan 2005). In asserting this uncertainty, he raises the concern that these principles, once exposed, might be discovered to be inadequate from a Western point of view. Other observers more generally have wondered whether oocyte donors for stem cell research are especially vulnerable to exploitation by scientists (Magnus and Cho 2005). For example, should women be afforded protections above and beyond what is normally provided for those who donate oocytes for purely medical or reproductive purposes? One possibility is that stem cell researchers in South Korea and elsewhere may tend to oversell the contribution oocyte donors make to stem cell research at the expense of adequately informing them of the known physical risks associated with oocyte procurement (Magnus and Cho 2005).

We agree that these concerns are of vital importance, and we believe that the consent process for somatic cell donation also demands careful ethical scrutiny. To help advance the social discourse over both oocyte and somatic cell donation, we describe in detail the donation consent procedures designed by one of the present authors specifically for the Hwang team at Seoul National University in early 2005. These guidelines were closely followed in the Korean research protocol that resulted in the recent derivation of eleven patient-specific pluripotent stem cell lines (Hwang et. al 2005). We also explain the ethical foundations of these new oocyte and somatic cell donation consent procedures, and propose ways of improving these guidelines for future stem cell research.

The South Korean experience with oocyte and somatic cell donation over the past year and a half has been fueled by the Hwang team’s earlier breakthrough in stem cell research (Hwang et al. 2004). Immediately after their February 2004 announcement that they had been the first to derive a pluripotent stem cell line from a cloned human blastocyst, Hwang and colleagues were inundated with emails and telephone calls from individuals who wanted to donate their oocytes and somatic cells for the next round of Hwang’s research. Given the sudden surfeit of potential oocyte and somatic cell donors, Hwang and colleagues called upon the help of one of the present authors, Kyu Won Jung, to design new guidelines for the consent process in order to meet the challenges posed by this high level of public enthusiasm.

With regard to oocyte donation, Jung added extra conditions to the requirements Korean scientists were obliged to follow. Since these added safeguards were first voluntarily put into action for the protocol which resulted in the Hwang team’s May 2005 Science publication, we outline the oocyte donation procedures below by reference to that experience.

Women seeking to donate their oocytes for stem cell research were required to advance successively through three independent informed consent processes prior to their being allowed to donate.

Oocyte Donor Consent Process - Step 1:

1. Volunteers were privately interviewed by a member of the research team.
2. Using supplementary documents, the researcher explained in detail to each volunteer the specific, non-therapeutic nature of the research and all the known risks associated with oocyte donation.
3. After verifying that the volunteer (i) understood the purpose of the research and the risks associated with oocyte donation, (ii) was not under the coercive influence of others, and (iii) was not under the illusion that the research was of a therapeutic nature, the researcher obtained the volunteer’s informed consent and signature.

Oocyte Donor Consent Process - Step 2:

1. Each volunteer was privately interviewed a second time by at least one IRB member.
2. No other individuals, including no research members, were allowed to attend this interview.
3. Using supplementary documents, the IRB member explained in detail the non-therapeutic nature of the research and all the known risks associated with oocyte donation.
4. Informed consent was obtained only after the IRB member determined that the volunteer (i) understood the purpose of the research and all the attendant physical risks, (ii) was not under the coercive influence of others, (iii) was not under the illusion that the research was of a therapeutic nature, and (iv) was not related to a family member who could benefit from downstream therapeutic applications of this research. The IRB member then signed the informed consent document containing the volunteer’s and the researcher’s signatures.
5. The volunteer was allowed to proceed to the medical screening process only after both the researcher and the IRB member(s) independently obtained her informed consent.

Oocyte Donor Consent Process – Step 3:

1. Only volunteers who had passed the first two consent processes were medically screened.
2. Screening was performed by the doctor performing the oocyte procurement procedure.
3. During the screening process, each volunteer was informed by the doctor of all known risks associated with oocyte donation, and each volunteer was required to give verbal consent for that procedure specifically.

This multi-stage consent procedure for oocyte donation was designed to protect the well being of oocyte donors and their liberty interests. After all three consent processes were completed by oocyte donors, the full IRB committee reviewed and approved of all signed informed consent documents and the results of each donor’s medical screening. While some critics have questioned whether Korean oocyte donors were adequately alerted to the physical risks associated with egg procurement (Magnus and Cho 2005), it is worth emphasizing that each donor was fully informed of all the attendant risks on three separate occasions by at least three different individuals.

In addition to the three-tiered mature of the consent process, what made this procedure particularly novel was the addition of Consent Process Step 2, which went far beyond the research requirements mandated by current Korean regulations. Step 2 added a layer of personal communication with prospective oocyte donors that was independent of the research team’s involvement and potential influence. It also provided an opportunity for dialogue with the prospective donor that was substantively different from the medically focused dialogue in Consent Process Step 3. In short, the purpose of Step 2 was to facilitate each volunteer’s carefully considered choice to donate her oocytes for research.

To help ensure that oocyte donors were acting of their own volition and initiative, two specific safeguards were incorporated into Consent Process Step 2 from the very start. First, any volunteers related to individuals with serious medical conditions were automatically disqualified from donating oocytes. To circumvent the possibility of social pressure from ill family members or by others on their behalf – a widespread cultural reality in Korean society – oocyte donors could not have a parent, sibling, child or spouse who might benefit from any potential downstream therapeutic applications. Second, the interviewing IRB member was given full discretion at any point to reject a volunteer if there was even the slightest suspicion that she did not fully appreciate the nature and scope of the research or the personal risks involved in oocyte donation, or that she was not acting completely on her own free will. Occasionally, psychological evaluations of some volunteers were ordered by the IRB member in an effort to clarify their degree of voluntariness and their motivations for donating their oocytes.

The informed consent procedure for somatic cell donation similarly was designed to protect the liberty interests and well-being of prospective cell donors. After February 2004, many patients at Seoul National University Hospital and Hanyang University Hospital asked their physicians if they could participate in the next round of Hwang’s stem cell research. After these physicians notified the Hwang team of their patient’s requests, the research team chose three medical conditions for further research: congenital hypogamma-globulinemia; spinal cord injury; and juvenile diabetes. The researchers then used the following multi-stage consent procedure to obtained somatic cell donations from individuals with one of the aforementioned medical conditions.

Somatic Cell Donor Consent Process - Step 1:

1. Interested patients were interviewed individually by a member of the research team.
2. Using supplementary documents, the researcher informed each volunteer of the non-therapeutic nature of the research protocol and the physical risks associated with cell donation, which took the form of a small skin biopsy just below the navel.
3. The researcher emphasized that the cell donor would not receive any intellectual or property rights that might be derived from the study, and that future therapeutic applications of the study could not be guaranteed.
4. After verifying that the volunteer understood the facts and was not under the coercive influence of others, the researcher obtained the volunteer’s informed consent and signature.
5. In the case that the patient was a minor, the patient’s parents were given all relevant information and both parents were required to sign the consent form on behalf of their child. The researcher also sought the assent of the minor when appropriate.

Somatic Cell Donor Consent Process – Step 2:

1. At least one IRB member interviewed volunteers who had been consented by the researcher.
2. Using supplementary documents, the IRB member again explained the nature and scope of the research and the physical risks associated with cell donation.
3. The IRB member also emphasized that the cell donor would not directly benefit from the research in any way and that therapeutic applications in the future could not be guaranteed.
4. After verifying that the volunteer understood the facts and was not under the coercive influence of others, the IRB member obtained the volunteer’s informed consent.

Somatic Cell Donor Consent Process 3:

1. The medical screening test was done by a physician.
2. Patients who passed the medical screening test were informed of the physical risks associated with cell procurement, and each patient provided verbal consent for that procedure specifically.

Like the multi-stage oocyte donation consent procedure, the somatic cell donation consent procedure called for an independent interview by at least one IRB member to clarify each volunteer’s understanding about his or her involvement in the study. Because interviewing IRB members also had monitoring responsibilities, their knowledge of potential donors’ identities was not a breach of confidentiality.

We acknowledge that the consent procedures for oocyte and somatic cell donation here described are works in progress; we believe these two procedures could be improved in various ways, although each proposed change raises new practical considerations. For example, we recommend that female researchers, female IRB members, and female physicians ought to interview volunteers throughout the oocyte donation consent process whenever possible (for oocyte donation in the May 2005 patient-specific stem cell study, the researcher and physician were both female and the IRB member was male). We suspect that many volunteers may find the interview environment at each stage of the oocyte consent process much more comfortable if they were prompted by another woman to discuss their motivations and concerns about oocyte donation. We are aware that perceived power differentials between research participants on the one hand and scientists, institutional representatives, and physicians on the other can create barriers to effective communication (Simon et al. 2003). The involvement of female interviewers throughout the oocyte donation consent process might help mitigate this possibility. Admittedly, this is just an assumption; empirical sociological research must be conducted to determine whether female interviewers would make a positive difference specifically in the informed consent procedure for oocyte donation in stem cell research.

Second, we believe that researchers and IRB members ought to explain to rejected potential oocyte donors why they were not selected to participate in research. Ideally, we suggest that counselors should be made available to meet with potential oocyte donors whose self-esteem may have been damaged as a result of their being denied the opportunity to donate their oocytes.

Our third recommendation is that, under certain circumstances, women ought to be allowed the opportunity to donate their oocytes for stem cell research in cases where they are related to patients who might benefit from possible therapeutic applications in the future. We believe this is ethically permissible as long as adequate safeguards can be implemented to ensure that oocyte donors are not operating under a therapeutic misconception about their own involvement in the research protocol, and that they are not improperly motivated by family pressure. There are two reasons for this change. First, tissue donations from individuals related to patients are ethically tolerated in contexts where the physical risks to the donor are far greater, such as kidney and bone marrow donation. There seems to be no reason in principle to disallow oocyte donation for stem cell research by donors who are related to patients, so long as donors understand the non-therapeutic nature of their involvement in this research. Second, future stem cell research protocols may target medical conditions for which mitochondrial DNA is a key factor and thus would require the use of paired groups of biologically-related egg and somatic cell donors. Rigidly insisting that oocyte donors not have a patient in the family would hinder these kinds of scientific studies.

Finally, we recommend that all oocyte donors should sign an informed consent document during their third consent process authorizing the physician to perform the oocyte procurement procedure itself, rather than simply providing verbal consent to this effect.

We also need to consider ways to improve the somatic cell donation consent procedure. Many critics have focused their attention on the exploitability of oocyte donors. In many ways, however, somatic cell donors may be equally, if not more, vulnerable. For instance, patients who decide to participate as cell donors commonly suffer from serious medical conditions for which politicians, the media, and some scientists have prematurely declared to be curable though further stem cell research.

One way of protecting patient volunteers would be to provide another interviewer along the consent procedure who has been trained to act in a role similar to that of a genetic counselor or a medical social worker. This “cell donation counselor” could work to ensure that the patient is not operating under a therapeutic misconception. Furthermore, the cell donation counselor could advise the patient of the important fact that his or her cell donation could result in a genetically-matched stem cell line which could be used for a plethora of scientific and even commercial purposes. If such a counseling interaction were included in addition to, or perhaps in lieu of, the IRB member’s interview, then practical questions about the training and funding for cell donation counselors would need to be addressed.

Like the oocyte donation procedure, the somatic cell donation procedure could benefit from well-designed sociological studies of individuals who volunteer to donate their tissues for stem cell research. What preconceptions and motivations do they bring to the process, and what level of information do they retain throughout the course of the consent procedure? What are their socio-economic backgrounds? Such data are currently missing. Empirical research is urgently needed to improve the design of oocyte and somatic cell donation consent procedures and to identify salient discussion points for both types of volunteers.

Finally, we recommend that all somatic cell donors should sign an informed consent document during their third consent process authorizing the physician specifically to collect a cell sample, rather than simply providing verbal consent to this effect.

In conclusion, the guidelines we have described for oocyte and somatic cell procurement aim to protect both kinds of donors from coercive social pressures and therapeutic misconceptions about their participation in stem cell research. We believe these multi-stage consent procedures provide a reasoned, yet still evolving, response to new problems in stem cell research ethics. We invite others to use these procedures as a basic template for SCNT stem cell research and to think about ways to improve these guidelines as needed.

References
Caplan, A. L. 2005. Stem cell research needs regulation: Cloning in S. Korea raises a host of questions. Accessed May 20, 2005 at http://www.bioethics.net/articles.php?viewCat=2&articleId=182.

Hwang, W. S., Y. J. Ryu, J. H. Park, et al. 2004. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 303: 1669-1674.

Hwang, W. S., S. I. Roh, B. C. Lee, S. K. Kang, et al. 2005. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science 308: 1777-1783.

Magnus, D., and M. K. Cho. 2005. Issues in oocyte donation for stem cell research. Science 308: 1747-1748.

Simon, C., S. Zyzanski, M. Eder, et al. 2003. Groups potentially at risk for making poorly informed decisions about entry into clinical trials for childhood cancer. Journal of Clinical Oncology 11: 2173-2178.